Vascular and metabolic diseases are, despite cancer, the leading causes of death in the western world. Although many different ways of treating vascular and metabolic diseases are known, there is still a need for improved medication. Life-style modifications and drug therapy can decrease and delay the morbidity and mortality associated with these diseases. Treatments which have been proven to reduce the risk for morbidity and mortality in vascular diseases have been typically shown to either improve impaired vascular function or to delay/prevent the progression of vascular dysfunction caused by hypertension, atherosclerosis or other classical metabolic risk factors. Examples for such treatments are calcium channel blockers, beta blockers, angiotension-enzyme converting inhibitors or angiotension receptor blockers.
In patients with atherosclerosis, who are suffering e.g. from angina pectoris, one of the established standard treatments involves treatment with organic nitrates, specifically nitrate esters, such as glyceryl trinitrate (nitroglycerine), isosorbide dinitrate, or penta-erythrityl tetranitrate, which act all as coronary vasodilators and improve symptoms and exercise tolerance. Most organic nitrates (e.g. mononitrates and trinitrates) are fast acting pharmaceuticals with a relatively short halflife and have the typical disadvantage that patients develop a nitrate tolerance, meaning that part of the pharmacodynamic effect is lost during chronic treatment and a three times daily dosing regimen.
In the case of peripheral arterial disease (PAD) which is typically caused by hypertension and atherosclerosis and presents clinically with intermittent claudication, compounds with vasodilating properties have been shown to improve symptoms and walking. Two established licensed compounds for treatment of PAD patients are cilostazol (a phospho-diesterase III inhibitor) and pentoxifylline. Cilostazol (U.S. Pat. No. 4,277,479) acts as a direct arterial vasodilator. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins, increasing plasma high density lipoprotein cholesterol and apolipoproteins.
Nitrate esters of drugs in general are described in WO 00/61357. Diazeniumdiolate derivatives have recently been recognized as alternatives for nitrates, setting free two molecules of NO under physiological conditions. A diazeniumdiolate derivative of tacrine is described by L. Fang et al., J. Med. Chem. 51, 7666-7669 (2008).